Metabolic Imbalance in Carbohydrate, Pyrimidine and Ornithine Utilization

Abstract

The behavior of opposing key enzymes and pathways involved in the metabolic imbalance in carbohydrate, pyrimidine and ornithine utilization was examined in nutritional and hormonal alterations and in normal and neoplastic proliferative conditions. 1. 1. In carbohydrate metabolism a marked imbalance emerged in the ratios of opposing key enzymes of gluconeogenesis and glycolysis, glucose-6-phosphatase/glucokinase, fructose-1,6-diphosphatase/phosphofructokinase, pyruvate carboxylase/pyruvate kinase in starvation, in diabetes and in insulin treatment. There were marked and progressive alterations in differentiation and in liver neoplasia but not in the regenerating liver. 2. 2. In pyrimidine and DNA metabolism, on the other hand, the antagonistic controls were revealed in major shifts in the balance of opposing pathways when gene expression was modulated by alterations in the replicative process in regenerating liver, in differentiation and in neoplasia. In starvation and in diabetes both synthetic and catabolic utilization of thymidine decreased and insulin restored pyrimidine metabolism to normal levels. 3. 3. In ornithine metabolism starvation caused a decrease, whereas diabetes resulted in an increase, in the activity of ornithine carbamyl transferase. Insulin administration in diabetic rats returned the enzyme activity to normal range. In differentiation ornithine carbamyl transferase activity increased, whereas in hepatomas it gradually decreased in parallel with an increase in tumor growth rate. 4. 4. The metabolic imbalance elucidated in the hepatomas confers a selective biological advantage on the cancer cells. 5. 5. The metabolic imbalance in nutritional, hormonal and normal and neoplastic proliferative conditions emerged as a result of ordered alterations in gene expression which operate, in part at least, through setting the amounts, activities and ratios of opposing key enzymes and metabolic pathways.